Of all identified diabetic sequelae, perhaps the most physiologically deleterious are those complications involving the cardiovascular system. These may, for example, involve the blood or nervous supply to the heart or the heart muscle (myocardium) directly. An associated disease state related to myocardial abnormalities is diabetic cardiomyopathy, an affliction in which subjects afflicted therewith manifest such symptomes as, inter alia, an overall reduction in cardiac performance, reduced ventricular compliance as characterized by slowed, incomplete cardiac filling (diastolic dysfunction), an increased incidence of congestive heart failure and a markedly enhanced potential for death during episodes of myocardial infarction. Moreover, secondary indicators such as the development of interstitial and myocellular tissue abnormalities (including interstitial, perivascular and focal scar-like connective tissue accumulations) may be present in addition to microangiopathy (including thickening of the capillary basement membrane, pericapillary edema and capillary microaneurysms). These characteristic abnormalities define the syndrome of diabetic cardiomyopathy. Detailed discussions of this condition may be found, for example, in F. S. Fein, et. al., "Diabetic Cardiomyopathy", Cardiovascular Drugs and Therapy, Vol. 8, pp. 65-73, 1994, and D. S. H. Bell, "Diabetic Cardiomyopathy", Diabetes Care, Vol. 18, pp. 708-714, 1995 and pertinent references cited therein.
Aldose reductase inhibitors constitute a class of compounds which have become well known for their utility in the treatment of certain diabetic complications such as ocular cataract formation and diabetic neuropathy and nephropathy. Such compounds are well known to those skilled in the art and may be identified by standard biological methodology.
The compound zopolrestat, 3,4-dihydro-4-oxo-3-(5-trifluoromethylbenzothiazol-2-ylmethyl)phthalazin-1 -ylacetic acid, is known, for example, from commonly assigned U.S. Pat. No. 4,939,140, the disclosure of which is hereby incorporated by reference, together with a number of related compounds, as having utility as aldose reductase inhibitors. Zopolrestat has the structure ##STR1## and, as an aldose reductase inhibitor, has utility in the treatment of certain complications arising from diabetes mellitus.
Other aldose reductase inhibitors are known to have use in the lowering of lipid levels in mammals, including humans. See, for example, U.S. Pat. No. 4,492,706 and EP 0 310 931 A2, as well as commonly assigned U.S. Pat. No. 5,391,551, the disclosures of which are also incorporated herein by reference.
Commonly assigned U.S. Pat. No. 5,064,830, the disclosure of which is hereby incorporated by reference, discloses the use of certain oxophthalazinyl acetic acids, including zopoirestat, for the lowering of blood uric acid levels.